We analyzed SARS-CoV-2 seroprevalence in a large, well-described representative Viennese cohort after an early governmental lockdown with respect to the occurrence of symptoms and household ...transmission. Participants of the LEAD Study, a population-based cohort study from Vienna, Austria, were invited along with their household members (April 20th to May20th 2020). Sera were analyzed using anti-SARS-CoV-2 immunoassay including a neutralization test as a confirmatory assay. A total of 12,419 individuals participated (5984 LEAD participants; 6435 household members), 163 (1.31%; 59 LEAD cohort members) of whom were SARS-CoV-2 antibody positive. The estimated number of COVID-19 cases projected from our findings by age and sex for Vienna was 21,504 (1.13%). Cumulative number of positively tested cases in Vienna until May 20th 2020 was 3020, hence 7.1 times (95% confidence interval 5.5-9.1) lower than projected. Relative risk (RR) of seropositivity by age was highest for children aged 6-9 years RR compared to age group 20-49: 1.21 (CI 0.37-4.01), lowest for ≥ 65 years RR 0.47 (CI 0.21-1.03). Half of the positive individuals developed no or mild symptoms. In a multivariate analysis, taste and smell disturbances were most strongly related to SARS-CoV-2 positivity. Infection probability within households with one confirmed SARS-CoV-2-specific antibody-positive person was 31%. Although seroprevalence was very low (1.13%) for a central European capital city, due to an early governmental lockdown, SARS-CoV-2 infections were more prevalent than officially reported polymerase chain reaction-positive cases. Of note, seroprevalence was highest in young children. Half of SARS-CoV-2 antibody-positive subjects had no or only mild symptoms. Taste and smell disturbances were most prominent, possibly guiding clinicians in diagnosing SARS-CoV-2 infection.
The airway epithelium plays a critical role in innate responses to airborne allergens by secreting IL-1 family cytokines such as IL-1α and IL-33 as alarmins that subsequently orchestrate appropriate ...immune responses. Previous studies revealed that epithelial IL-33 secretion by allergens such as
or house dust mite involves Ca
-dependent signaling, via initial activation of ATP-stimulated P2YR2 (type 2 purinoceptor) and subsequent activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase DUOX1. We sought to identify proximal mechanisms by which epithelial cells sense these allergens and here highlight the importance of PAR2 (protease-activated receptor 2) and TRP (transient receptor potential) Ca
channels such as TRPV1 (TRP vanilloid 1) in these responses. Combined studies of primary human nasal and mouse tracheal epithelial cells, as well as immortalized human bronchial epithelial cells, indicated the importance of both PAR2 and TRPV1 in IL-33 secretion by both
and house dust mite, based on both pharmacological and genetic approaches. TRPV1 was also critically involved in allergen-induced ATP release, activation of DUOX1, and redox-dependent activation of EGFR (epidermal growth factor receptor). Moreover, genetic deletion of TRPV1 dramatically attenuated allergen-induced IL-33 secretion and subsequent type 2 responses in mice
. TRPV1 not only contributed to ATP release and P2YR2 signaling but also was critical in downstream innate responses to ATP, indicating potentiating effects of P2YR2 on TRPV1 activation. In aggregate, our studies illustrate a complex relationship between various receptor types, including PAR2 and P2YR2, in epithelial responses to asthma-relevant airborne allergens and highlight the central importance of TRPV1 in such responses.
In myeloid cells the inflammasome plays a crucial role in innate immune defenses against pathogen- and danger-associated patterns such as crystalline silica. Respirable mineral particles impinge upon ...the lung epithelium causing irreversible damage, sustained inflammation and silicosis. In this study we investigated lung epithelial cells as a target for silica-induced inflammasome activation.
A human bronchial epithelial cell line (BEAS-2B) and primary normal human bronchial epithelial cells (NHBE) were exposed to toxic but nonlethal doses of crystalline silica over time to perform functional characterization of NLRP3, caspase-1, IL-1β, bFGF and HMGB1. Quantitative RT-PCR, caspase-1 enzyme activity assay, Western blot techniques, cytokine-specific ELISA and fibroblast (MRC-5 cells) proliferation assays were performed.
We were able to show transcriptional and translational upregulation of the components of the NLRP3 intracellular platform, as well as activation of caspase-1. NLRP3 activation led to maturation of pro-IL-1β to secreted IL-1β, and a significant increase in the unconventional release of the alarmins bFGF and HMGB1. Moreover, release of bFGF and HMGB1 was shown to be dependent on particle uptake. Small interfering RNA experiments using siNLRP3 revealed the pivotal role of the inflammasome in diminished release of pro-inflammatory cytokines, danger molecules and growth factors, and fibroblast proliferation.
Our novel data indicate the presence and functional activation of the NLRP3 inflammasome by crystalline silica in human lung epithelial cells, which prolongs an inflammatory signal and affects fibroblast proliferation, mediating a cadre of lung diseases.
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which was initially known to be highly activated by oxidative stress-induced DNA strand breaks, has been shown to be involved in the ...pathophysiology of acute and chronic inflammatory diseases. PARP-1 deficiency in mice led to the discovery of its coactivating function in the nuclear factor-kappa B-mediated gene expression and in addition, pharmaceutical inhibition of PARP-1 was shown to reduce the production of inflammatory mediators. In this study, the in vitro PARP-1-inhibiting effect of various flavonoids was investigated. The flavonoids myricetin, tricetin, gossypetin, delphinidin, quercetin, and fisetin were identified as significant inhibitors of the purified enzyme. Further evaluation of these compounds in N-methyl-N'-nitro-N-nitrosoguanidine-treated human pulmonary epithelial cells showed that the formation of the poly(ADP-ribose) polymers, as well as the decreased NAD⁺ levels, was reduced by quercetin, fisetin, and tricetin. Finally, IL-8 production of LPS-stimulated human pulmonary epithelial cells could be significantly reduced by these flavonoids. The results of this study indicate that specific flavonoids have PARP-1-inhibiting activity in addition to the earlier described antioxidant effects. PARP-1 inhibition and preservation of cellular NAD⁺ and energy production could play a role in the antiinflammatory activity of these specific flavonoids. In addition, these results indicate additional mechanisms by which flavonoids can exert antiinflammatory activity. Furthermore, these results indicate possibilities to use food-derived flavonoids in the treatment of chronic inflammatory diseases.
In previous post hoc analyses of the WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) study in patients with severe COPD on dual bronchodilation using the 9-month ...treatment interval after ICSs had been withdrawn, eosinophil thresholds of 300 and 400 cells/ml (approximately 20 and 11% of the overall WISDOM population, respectively) identified patients with more exacerbations after withdrawal of ICS (5). A negative binomial regression model was used to estimate the moderate or severe exacerbation rate ratio over the 9 months after complete withdrawal of ICSs. ...although the greater than or equal to 400 cells/ml threshold provides the greatest confidence that patients will benefit from ICSs, our data indicate that patients with eosinophil counts between 300 and 400 cells/ml will also benefit from additional ICS treatment. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary.
Abstract Background The German COPD cohort study COSYCONET (“ CO PD and SY stemic consequences- CO morbidities NET work”) investigates the interaction of lung disease, comorbidities and systemic ...inflammation. Recruitment took place from 2010-2013 in 31 study centers. In addition to the baseline visit, follow-up visits are scheduled at 6, 18, 36 and 54 months after baseline. The study also comprises a biobank, image bank, and includes health economic data. Here we describe the study design of COSYCONET and present baseline data of our COPD cohort. Methods Inclusion criteria were broad in order to cover a wide range of patterns of the disease. In each visit, patients undergo a large panel of assessments including e.g. clinical history, spirometry, body plethysmography, diffusing capacity, blood samples, 6-minute walk-distance, electrocardiogram and echocardiography. Chest CTs are collected if available and CTs and MRIs are performed in a subcohort. Data are entered into eCRFs and subjected to several stages of quality control. Results Overall, 2741 subjects with a clinical diagnosis of COPD were included (59% male; mean age 65±8.6 years (range 40-90)). Of these, 8/35/32/9% presented with GOLD stages I-IV; 16% were uncategorized, including the former GOLD-0 category. 24% were active smokers, 68% ex-smokers and 8% never-smokers. Data completeness was 96% for the baseline items. Conclusion The German COPD cohort comprises patients with advanced and less advanced COPD. This is particularly useful for studying the time course of COPD in relation to comorbidities. Baseline data indicate that COSYCONET offers the opportunity to investigate our research questions in a large-scale, high-quality dataset.
Outcomes other than spirometry are required to assess nonbronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the ...6-minute-walk distance (6MWD) have been derived from narrow cohorts using nonblinded intervention.
To determine minimum clinically important difference for change in 6MWD over 1 year as a function of mortality and first hospitalization in an observational cohort of patients with COPD.
Data from the ECLIPSE cohort were used (n = 2,112). Death or first hospitalization were index events; we measured change in 6MWD in the 12-month period before the event and related change in 6MWD to lung function and St. George's Respiratory Questionnaire (health status).
Of subjects with change in the 6MWD data, 94 died, and 323 were hospitalized. 6MWD fell by 29.7 m (SD, 82.9 m) more among those who died than among survivors (P < 0.001). A reduction in distance of more than 30 m conferred a hazard ratio of 1.93 (95% confidence interval, 1.29-2.90; P = 0.001) for death. No significant difference was observed for first hospitalization. Weak relationships only were observed with change in lung function or health status.
A reduction in the 6MWD of 30 m or more is associated with increased risk of death but not hospitalization due to exacerbation in patients with chronic obstructive pulmonary disease and represents a clinically significant minimally important difference.
The aim of the present study was to profile a multidimensional response to pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD).Dyspnoea, exercise performance, ...health status, mood status and problematic activities of daily life were assessed before and after a 40-session pulmonary rehabilitation programme in 2068 patients with COPD (mean forced expiratory volume in 1 s of 49% predicted). Patients were ordered by their overall similarity concerning their multidimensional response profile, which comprises the overall response on MRC dyspnoea grade, 6MWD, cycle endurance time, Canadian Occupational Performance Measure performance and satisfaction scores, Hospital Anxiety and Depression Scale anxiety and depression, and St George's Respiratory Questionnaire total score, using a novel non-parametric regression technique.Patients were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%; "very good responder"), n=742 (35.9%; "good responder"), n=731 (35.4%; "moderate responder"), and n=217 (10.5%; "poor responder"). Patients in the "very good responder" cluster had higher symptoms of dyspnoea, number of hospitalisations <12 months, worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, worse health status, and a higher proportion of patients following an inpatient PR programme compared to the other three clusters.A multidimensional response outcome needs to be considered to study the efficacy of pulmonary rehabilitation services in patients with COPD, as responses to regular outcomes are differential within patients with COPD.
The global increase in the prevalence and incidence of obesity has called serious attention to this issue as a major public health concern. Obesity is associated with many chronic diseases, including ...cardiovascular disease and diabetes, and recently the role of overweight and obesity in lung disease has received new interest. Independently of obesity, diet also plays a role as a risk factor for many chronic diseases, and evidence is accumulating to support a role for diet in the prevention and management of several lung diseases. Chronic obstructive lung disease is the third-leading cause of death globally, and both obesity and diet appear to play roles in its pathophysiology. Obesity has been associated with decreased lung-function measures in population-based studies, with increased prevalence of several lung diseases and with compromised pulmonary function. In contrast, obesity has a protective effect against mortality in severe chronic obstructive pulmonary disease (COPD). Nutrient intake and dietary patterns have also been associated with lung-function measures and the development and progression of COPD. Taken together, this suggests that a focus on obesity and diet should be part of public health campaigns to reduce the burden of lung disease, and could have important implications for clinicians in the management of their patients. Future research should also focus on elucidating these relationships in diverse populations and age-groups, and on understanding the complex interaction between behavior, environment, and genetics in the development and progression of COPD. The goal of this article is to review current evidence regarding the role that obesity and diet play in the development of COPD, and in COPD-related outcomes.
Personalised pulmonary rehabilitation in COPD Wouters, Emiel F M; Wouters, Birgit B R E F; Augustin, Ingrid M L ...
European respiratory review,
03/2018, Letnik:
27, Številka:
147
Journal Article
Recenzirano
Odprti dostop
This review summarises ongoing developments in personalised medicine and individualised medicine in chronic obstructive pulmonary disease (COPD). Currently applied classification systems largely ...ignore the complexity and heterogeneity of the COPD syndrome. Personalised medicine has to consider the influence of unique circumstances of the person, which contribute to this heterogeneity and complexity. Pulmonary rehabilitation is described as a comprehensive, individualised intervention based on thorough assessment of identifiable treatable traits. Partnership in care will become a crucial factor to improve and maintain health. Tolerating uncertainty and unpredictability will enrich future doctor-patient relationships.
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